Background Reinforcing effects of cocaine arise through release of dopamine (DA) in the nucleus accumbens by neurons that project from the ventral tegmental area (VTA). In contrast, elevated levels of acetylcholine (ACh) in the nucleus accumbens may inhibit appetitive behaviors, including drug-seeking. Mammalian brain contains two forms of cholinesterase, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The physiologic role of BuChE is unclear, but it can metabolize cocaine and other exogenous compounds and contributes to degradation of ACh. Cholinesterase inhibitors such as tacrine increase synaptic levels of ACh by preventing its inactivation by AChE or BuChE, and can improve learning and memory. In animals, treatment with these agents can attenuate cocaine-reinforced behavior. We recently observed that pretreatment with certain cholinesterase inhibitors (tacrine or donepezil, but not rivastigmine) can produce long-lasting reductions in cocaine-motivated behavior in rats, described as persistent attenuation (PA). After outbred rats receive 10 mg/kg-day of tacrine, cocaine-reinforced behavior is decreased by more than 70% in one-half of the animals, with this change persisting for two weeks or longer after the last dose of cholinesterase inhibitor (PA-positive rats). Cocaine self-administration is unchanged in the remaining animals (PA-negative rats). Both tacrine and donepezil which cause PA have been associated with increases in brain levels of DA. While it can produce comparable cholinergic signs to tacrine or donepezil, administration of rivastigmine does not cause PA and does not increase DA in hippocampal dialysate. Pretreatment with an MAO (monoamine oxidase) inhibitor alone, can decrease cocaine self-administration by more than 60%, but does not cause PA (cocaine self-administration returns to baseline within one session). This finding shows that an increase in DA and other monoamines without cholinergic activation is not sufficient to cause PA. Additional preliminary studies showed that PA does not occur in cocaine-experienced rats that receive tacrine during a period when cocaine is not self-administered. Rationale Our hypothesis is that three elements must be combined to produce PA: 1.) Activation of ACh receptors in the nucleus accumbens; 2.) Activation of DA receptors in the same brain region; and 3.) At least some contingent self-administration of cocaine, even if present at a low level. If so, PA may be produced in patients after pretreatment with combinations of clinically available agents which activate these receptors, such as rivastigmine and bupropion. Because of the large and long-lasting reductions of cocaine-reinforced behavior in animals exhibiting PA, it may lead to improved medications for substance abuse disorders which are effective after short-term treatment. Aims For long-lasting decreases in cocaine reinforcement: 1.) Characterize cocaine aversiveness, neuronal activation, and levels of ACh, DA, and cocaine; 2.) Assess the role of DA and selectivity for D1- and D2- like receptors; 3.) Compare the effectiveness of agonists that are selective for nicotinic or muscarinic receptors. Methods Rats will be trained to respond under a multiple, alternating schedule of liquid-food reinforcement and self-administration of intravenous cocaine, and will also make a series of mutually-exclusive choices to receive either reinforcer. We will characterize brain concentrations of cocaine, DA, and ACh in rats that exhibit persistent reductions in cocaine self-administration (PA). Cocaine-induced activation of fos-immunoreactive neurons will be compared in rats that either exhibit PA or actively self-administer cocaine, for brain regions associated with reinforced and aversive behaviors. DA- and ACh- receptor selectivity of agents producing long-term reductions in cocaine-reinforced behavior will also be determined. Aversive effects of cocaine will be assessed by allowing rats to make mutually-exclusive choices for drug or food reinforcement and measuring their proximity to levers used to obtain either reinforcer.